tbuckley/cabot-search huggingface dataset:
Abstract 3194: Cancer-associated fibroblast heterogeneity in neuroblastoma
Authors: Nicolas B. Peterson, Paul G. Thomas
Journal: Cancer Research (2022)

Abstract Extracellular matrix (ECM) remodeling is a critical process within the solid tumor microenvironment. Cancer associated fibroblasts (CAFs) are the primary producers of matrix proteins and remodeling enzymes that cross-link and degrade matrix proteins. CAFs are enigmatic in that they can promote or impede tumor growth, suggesting heterogeneity that is not completely understood. How CAF heterogeneity evolves over tumor progression and how this evolution impacts ECM remodeling within solid tumors remain an outstanding question across cancer models. Recent studies have focused on CAF function in models of adult cancer, but little attention has been directed toward understanding CAF heterogeneity and ECM remodeling in childhood cancers, which are etiologically different diseases. Neuroblastoma (NB) is a childhood cancer of neuroendocrine cells that accounts for 15% of pediatric cancer deaths. Like other solid tumors, the NB tumor microenvironment includes malignant cells, CAFs, and immune cells. Our laboratory studies NB using a penetrant, spontaneous model of NB (TH-MYCN, AlkF1178L/+) in immunocompetent mice, allowing in vivo investigation of the tumor immune microenvironment from tumorigenesis to progressive disease. Using this model, we previously demonstrated the pro-tumorigenic role of macrophages and CD4+ T cells by showing that their depletion significantly reduced the formation of tumors and extended survival. In this study, 10X Chromium gene expression analysis of stromal cells from nascent and mature tumors identified two distinct subsets of CAFs characterized by alpha smooth muscle actin (Acta2) and Wilms tumor 1 (Wt1) expression. Interestingly, only Wt1 CAFs expressed chemokines and cytokines involved in recruitment of myeloid and T cells. Wt1 CAFs were enriched in the early tumor microenvironment and expressed genes encoding ADAMTS enzymes involved in degradation of the proteoglycan versican. Our preliminary findings indicate that Wt1 CAFs may be a crucial early recruiter of pro-tumorigenic immune cells in our model of neuroblastoma. Citation Format: Nicolas B. Peterson, Paul G. Thomas. Cancer-associated fibroblast heterogeneity in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3194.
Real-world incidence and impact of pneumonitis in patients with lung cancer treated with immune checkpoint inhibitors: a multi-institutional cohort study
Authors: Bruce C Tiu, Leyre Zubiri, James Iheke, Vartan Pahalyants, Nicholas Theodosakis, Pearl Ugwu-Dike, Jayhyun Seo, Kimberly Tang, Meghan E Sise, Ryan Sullivan, Jarushka Naidoo, Meghan J Mooradian, Yevgeniy R Semenov, Kerry L Reynolds
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Immune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts. Methods A combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP. Results The attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1–7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71). Conclusions In a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.
Abstract 2418: Markers for metastasis evaluation of the ErbB family and GDF15 inratosteosarcoma
Authors: Shun Ishiyama, Bailey West, Hyo-Jeong Han, Xin Guo, Tomoaki Ito, Harumi Saeki, Malcolm V. Brock, Kathleen Gabrielson
Journal: Cancer Research (2022)

Abstract The most recent advance in the treatment of osteosarcoma (OS) occurred in the 1980s when multi-agent chemotherapy was shown to improve overall survival compared to surgery alone. Animal model investigations can accelerate the understanding of human diseases and since few models are available for OS, we refined a rat model to ask questions regarding pathways of metastasis and metastasis biomarker predictiveness. The outbred Sprague-Dawley (SD) rat model is an immunocompetent, syngeneic model, as we implant UMR106 OS cells (ATCC), which were originally isolated from a SD OS. We developed a reproducible method to orthotopically implant cells into the tibia microenvironment and to amputate the limb for longitudinal studies. Using young rats, we also modeled pediatric OS. We found that rats develop reproducible primary and metastatic pulmonary tumors which histologically resemble human primary and metastatic osteosarcoma. Using immunohistochemistry methods, we found that primary OS is infiltrated with numerous macrophages with relatively fewer CD3+ T cells. A protein expression survey of these OS cells revealed significant expression of ErbB family receptor tyrosine kinases (ErbB2, ErbB4), which have recently been shown to be anti-inflammatory against macrophages. We also discovered that rats with osteosarcoma have markedly high serum levels of Growth Differentiation Factor 15 (GDF15), also called Macrophage Inhibitory Cytokine 1, a member of the TGF beta family of proteins, which is also frequently expressed with ErbB2 in cancers. GDF15 was measured by ELISA. Western blot analysis showed that GDF15 precursor (pro-peptide) was expressed in primary and metastases. This model will enable studies with anti-ErbB2 or GDF15 pathway inhibition to assess the role of macrophage activation in the setting of pathway inhibition and chemotherapy, as well as how pathway inhibition modulates metastasis incidence. In vivo and invitro, systems will enable the assessment of the role of GDF15 as a potential biomarker of metastasis, compared to tibial radiographic patterns, serum alkaline phosphatase, and lung histopathology. In conclusion, we have an immunocompetent, syngeneic orthotopic osteosarcoma rat model which affectively resembles human osteosarcoma, and can be used for better understanding metastasis mechanisms and metastasis biomarkers. Citation Format: Shun Ishiyama, Bailey West, Hyo-Jeong Han, Xin Guo, Tomoaki Ito, Harumi Saeki, Malcolm V. Brock, Kathleen Gabrielson. Markers for metastasis evaluation of the ErbB family and GDF15 inratosteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2418.
Abstract 1649: Humanized PVRIG mice: A novel tool for evaluating anti-PVRIG immunotherapies
Authors: Yifu Zhang, Jiawei Yao, Rebecca Soto, Chonghui Liu, Qingcong Lin
Journal: Cancer Research (2022)

Abstract The use of humanized mouse models provides a promising platform for preclinical studies aimed at developing novel immunotherapies. While current checkpoint inhibitors have improved patient outcomes, combination therapy targeting additional checkpoint receptors may heighten the immune response. Specifically, previous reports have shown that high expression of the immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) protein leads to T-cell exhaustion. Furthermore, in vitro blockade of human PVRIG enabled T-cell activation. To explore the translational potential of inhibiting PVRIG, we evaluated the efficacy of PVRIG antibodies by generating a humanized B-hPVRIG mouse model. In this model, the mouse Pvrig gene was replaced by the human counterpart, and expression of the human PVRIG protein was confirmed in homozygous B-hPVRIG mice. Additionally, flow cytometry analysis showed similar distribution of T-cell subtypes within the blood, spleen, and lymph nodes of B-hPVRIG mice compared to wild-type C57BL/6. Lastly, our in vivo efficacy studies showed that homozygous B-hPVRIG mice that were subcutaneously implanted with murine colon cancer (MC38) cells and treated with 30 mg/kg of the human PVRIG antibody, reached a tumor growth inhibition (TGI) of approximately 40%. This data suggests that human PVRIG antibodies significantly inhibit tumor growth in homozygous B-hPVRIG mice. Altogether, our humanized B-hPVRIG mouse model is an effective tool for in vivo efficacy studies aimed at the development of novel PVRIG immunotherapies. Citation Format: Yifu Zhang, Jiawei Yao, Rebecca Soto, Chonghui Liu, Qingcong Lin. Humanized PVRIG mice: A novel tool for evaluating anti-PVRIG immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1649.
Abstract 5804: The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function
Authors: Mingquan zhang, Peng huang
Journal: Cancer Research (2022)

Abstract The activation of oncogenic K-ras by mutations may stimulate multiple cellular processes including lipids modification. However, the mechanisms by which K-ras affects lipid metabolism remain poorly understood. In this study, we found that PLA2G2A, an enzyme that hydrolyzes membrane phospholipids at sn-2 position to release polyunsaturated fatty acids (PUFA), was up-regulated by K-ras activation and its high expression was correlated with poor survival of patients with pancreatic ductal adenocarcinoma (PDAC). Abrogation of PLA2G2A by siRNA silencing or pharmacological inhibition significantly suppressed the proliferation of K-ras-driven cancer cells, as evidenced by inhibition of cell growth and loss of colony formation capacity. Suppression of PLA2G2A could also decrease K-ras-driven PDAC cell migration. Mechanistic study showed that PLA2G2A inhibition rendered cells vulnerability to lipid peroxidation, likely due to accumulation of excessive PUFA in the membranes. Such alterations resulted in membrane damage and mitochondrial dysfunction with elevated ROS, leading to a reduction in energy production and a decrease in acetyl-CoA, which further compromised de novo lipid biosynthesis. Our study suggests that PLA2G2A-mediated cell membrane remodeling plays an important role in cell survival and proliferation in during K-ras-driven cancer, and that PLA2G2 could be a potential therapeutic target for pancreatic cancer treatment. Citation Format: Mingquan zhang, Peng huang. The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5804.
Abstract 834: Serine protease hepsin regulates tumor growth via TGFbeta-EGFR signaling axis
Authors: Topi A. Tervonen, Denis Belitškin, Pauliina Munne, Shishir M. Pant, Ilida Suleymanova, Kati Belitškina, Jeroen Pouwels, Juha Klefström
Journal: Cancer Research (2022)

Abstract Hepsin (encoded by HPN gene) is a type II transmembrane serine protease, which is commonly overexpressed in carcinomas of prostate and breast. Hepsin protein is known to be stabilized by Ras-MAPK pathway signaling, and downstream, this protease regulates the degradation of extracellular matrix (ECM) components and activates growth factor pathways, including hepatocyte growth factor (HGF) and transforming growth factor beta (TGF beta) pathway. However, the impact of the hepsin-dependent signaling on cell proliferation and tumor growth is not well-understood. Therefore, we sought to clarify the role of hepsin during these events using engineered breast cancer cell lines, Hpn CRISPR knockout mouse model crossed with Wap-Myc breast cancer mouse model, and patient-derived explant cultures (PDEC)s from human breast tumors. We isolated Wap-Myc; Hpn-/- mammary tumor cells and made orthotopic transplantation into syngeneic wild-type recipient mice. The resulting Wap-Myc tumors that lack hepsin had reduced size both in primary and metastatic site compared to tumors derived from Wap-Myc; Hpn+/+ tumor cells. This decrease in growth was accompanied by downregulation in TGF beta and EGFR signaling as well as substantial reduction in total EGFR protein level. We further demonstrated that in 3D culture conditions overexpression of hepsin induced cell proliferation, which was TGF beta 1 and EGFR signaling-dependent, while PDECs treated with hepsin inhibitory antibodies and small molecules had decreased EGFR and TGF beta signaling activity and reduction in proliferation marker expression. Taken together, this study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGF beta and EGFR pathways and may provide an interesting druggable upstream target to inhibit TGF beta and EGFR pathways in breast cancer. Citation Format: Topi A. Tervonen, Denis Belitškin, Pauliina Munne, Shishir M. Pant, Ilida Suleymanova, Kati Belitškina, Jeroen Pouwels, Juha Klefström. Serine protease hepsin regulates tumor growth via TGFbeta-EGFR signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 834.
CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway
Authors: Nunzio Del Gaudio, Antonella Di Costanzo, Ning Qing Liu, Lidio Conte, Carmela Dell’Aversana, Guglielmo Bove, Rosaria Benedetti, Liliana Montella, Fortunato Ciardiello, Vincenzo Carafa, Concetta Ambrosino, Valeria Tucci, Mariarosaria Conte, Joost H. A. Martens, Hendrik G. Stunnenberg, Angela Nebbioso, Lucia Altucci
Journal: Molecular Cancer (2022)

Abstract Background The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear. Methods We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype. Results We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34 + cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression. Conclusions Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.
Abstract 2889: Novel bispecific humanized BCMA-CD3 antibodies specifically target multiple myeloma cells
Authors: Yanwei Huang, John Sienkiewicz, Jinying Sun, Liselle Guiang, Feng Li, Liming Yang, Lijun Wu, Vita M. Golubovskaya
Journal: Cancer Research (2022)

Abstract BCMA antigen is overexpressed in multiple myeloma cells and has been shown to be a promising target for novel cellular and antibody therapeutics. The humanized BCMA (clone 4C8A) antibody that effectively targeted multiple myeloma in a CAR (chimeric antigen receptor) format was used for designing several formats of bispecific BCMA-CD3 antibodies. Several different designs including univalent and bivalent BCMA-CD3 CrossMAB; triple chain BCMA-FAB-CD3 ScFv-Fc and tetravalent BCMA ScFv-CD3 ScFv-Fc antibodies were tested for affinity and binding with BCMA-positive cells and T cells. Real time cytotoxic activity (RTCA) and IFN-gamma secretion were also tested with multiple myeloma and CHO-BCMA target cells. All BCMA bispecific antibody designs demonstrated specific affinity with CHO-BCMA but not CHO cells in the nanoM range of 0.3-33 nM; all designs bound to T cells by FACS. The triple chain BCMA-FAB-CD3 ScFv-Fc designs had the highest Kd of binding with CHO-BCMA cells (Kd=0.3 nM) and with multiple myeloma MM1S, and H929 cells (0.1 and 0.3 nM, respectively). All antibodies with T cells specifically killed CHO-BCMA and multiple myeloma cells in a dose-dependent manner but not CHO or K562 cells, measured by RTCA assay. The bivalent BCMA-CD3 CrossMAB and triple chain BCMA FAB CD3scFv-Fc antibodies with T cells secreted IFN-gamma with EC50 =0.01-0.02 nM. In addition, the BCMA bispecific antibodies had high in vivo efficacy using a MM1S xenograft NSG mouse model. Significance: This data demonstrates high efficacy of novel hBCMA-CD3 antibodies with multiple myeloma cells and provides a basis for future pre-clinical and clinical development. Citation Format: Yanwei Huang, John Sienkiewicz, Jinying Sun, Liselle Guiang, Feng Li, Liming Yang, Lijun Wu, Vita M. Golubovskaya. Novel bispecific humanized BCMA-CD3 antibodies specifically target multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2889.
Abstract 5520: AK129, an anti-PD1/LAG-3 bi-specific antibody for cancer therapy
Authors: Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Chunshan Jin, Na Chen, Dennis Xia, Peng Zhang, Max Wang, Michelle Xia, Baiyong Li
Journal: Cancer Research (2022)

Abstract Background: AK129 is a bi-specific antibody acts by co-blocking two immune checkpoint molecules co-expressed on T cells, PD-1 and LAG-3. Signaling through PD-1/PD-L1 exerts major effects on cytokines production by T cells, inhibiting production of IFN-γ and IL-2. LAG-3 is a cell surface molecule expressed on effector T cells and Tregs, which plays a vital role in regulating T cell function to promote tumoral immune escape. LAG-3 and PD-1 mediate different signaling pathways, but they may act synergistically to cause effector T cell inactivation and exhaustion. AK129 is being investigated as a cancer immunotherapeutic agent. Methods: The antigen binding activity of AK129 to PD-1 and LAG-3 were measured by ELISA and FACS. In reporter gene assay, the bioactivities of AK129 to block the interaction of PD-1 with PD-L1 and to neutralize LAG-3-mediated activity were determined. The bioactivity of AK129 to enhance IL-2 and IFN-γ production in PBMCs via blockade of PD-1 and PD-L1/2 interaction were determined by using cellular assays. In in-vivo pharmacology studies, anti-tumor activity of AK129 was investigated in BALB/c-hPD1/hLAG3 mice bearing CT26.WT tumor model. Results: AK129 showed good antigen binding to PD-1 and LAG-3. AK129 potently inhibited the binding of LAG-3 to its ligand MHC-II, and the binding of PD-1 to its ligand PD-L1, thus blocking downstream immune suppression. At the individual target level, AK129 demonstrated a similar PD-1 blocking activity compared to penpulimab, and similar LAG-3 blocking activity compared to relatlimab. Importantly, at the whole cell level, the enhancement effect of AK129 is stronger than the combination of penpulimab and relatlimab, as evidenced by significantly higher level of IL-2 and IFN-γ secretion from PBMCs. AK129 showed favorable anti-tumor activity in BALB/c-hPD1/hLAG3 mice bearing CT26.WT tumor model, with tumor growth inhibition values reaching 99.27% and 89.48% in high dose (20 mg/kg) and low dose (4 mg/kg) group of AK129, respectively. Conclusion: AK129 is a dual checkpoint blocking bispecific antibody with design features similar to the PD-1/CTLA-4 bispecific antibody AK104, which demonstrated efficacy similar to PD-1 and CTLA-4 antibody combo and much improved safety profile. AK129 has demonstrated robust anti-tumor activity in both in vivo and in vitro pre-clinical studies, and with enhanced T cell activity compared to PD-1 and LAG-3 antibody combo. The efficacy and safety of AK129 await testing in the clinic. Citation Format: Zhaoliang Huang, Xinghua Pang, Tingting Zhong, Chunshan Jin, Na Chen, Dennis Xia, Peng Zhang, Max Wang, Michelle Xia, Baiyong Li. AK129, an anti-PD1/LAG-3 bi-specific antibody for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5520.